Intermediates for synthesizing pharmaceutically active 3, 7-diazabicyclo-(3,3,1)-nonane compounds

Schoen, Uwe; Hachmeister, Bernd; Kehrbach, Wolfgang; Kuehl, Ulrich; Buschmann, G

doi:10.1016/s0306-3623(88)80034-x

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“…As part of our research program related to the synthesis of specific bradycardic agents, we decided to synthesize 3,7-diazabicyclo[3.3.1]nonane derivatives with a new cardiovascular profile. Within this field, we have focused our interest on the synthesis of 3,7,9,9-tetraalkylbispidine derivatives (see Table listing the synthesized compounds and Scheme for general structures). The synthesis, pharmacological characterization, and quantitative structure−activity relationship (QSAR) analyses of 3,7,9,9-tetraalkyl-3,7-diazabicyclo[3.3.1]nonane derivatives will be described, leading to 6 (tedisamil, KC8857) as the most promising compound selected for clinical development.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Pharmacological Characterization, and Quantitative Structure−Activity Relationship Analyses of 3,7,9,9-Tetraalkylbispidines: Derivatives with Specific Bradycardic Activity

Schön¹,

Antel²,

Brückner³

et al. 1998

J. Med. Chem.

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A series of 3,7,9,9-tetraalkyl-3,7-diazabicyclo[3.3.1]nonane derivatives (bispidines) was synthesized and identified as potential antiischemic agents. Pharmacological experiments in vitro as well as in vivo are described, and the results are listed. For selection of those compounds fitting best to the desired profile of a specific bradycardic antianginal agent--decrease in heart rate without affecting contractility and blood pressure--these results were scored and ranked. Quantitative structure--activity relationship (QSAR) analyses were performed and discussed a posteriori by means of Hansch, nonelementary discriminant and factor analysis to get insight into the molecular features determining the biological profile. Highly significant equations were obtained, indicating hydrophobic and steric effects. Both pharmacological ranking and QSAR considerations showed compound 6 as the optimum within the structural class under investigation. Compound 6 (tedisamil, KC8857) has been selected as the most promising compound and was chosen for further pharmacological and clinical investigations as an antiischemic drug.

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Section: Introductionmentioning

confidence: 99%